11β-HSD1 determines the extent of muscle atrophy in a model of acute exacerbation of COPD

Webster, JM, Waaijenberg, K, van de Worp, WRPH, Kelders, MCJM, Lambrichts, S, Martin, C, Verhaegen, F, Van der Heyden, B, Smith, C, Lavery, GG ORCID: https://orcid.org/0000-0001-5794-748X, Schols, AMWJ, Hardy, RS and Langen, RCJ, 2023. 11β-HSD1 determines the extent of muscle atrophy in a model of acute exacerbation of COPD. AJP - Lung Cellular and Molecular Physiology, 324 (4), L400-L412. ISSN 1040-0605

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Abstract

Muscle atrophy is an extrapulmonary complication of acute exacerbations (AE) in chronic obstructive pulmonary disease (COPD). The endogenous production and therapeutic application of glucocorticoids (GCs) have been implicated as drivers of muscle loss in AE-COPD. The enzyme 11 β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates GCs and contributes toward GC-induced muscle wasting. To explore the potential of 11βHSD1 inhibition to prevent muscle wasting here, the objective of this study was to ascertain the contribution of endogenous GC activation and amplification by 11βHSD1 in skeletal muscle wasting during AE-COPD. Emphysema was induced by intratracheal (IT) instillation of elastase to model COPD in WT and 11βHSD1/KO mice, followed by vehicle or IT-LPS administration to mimic AE. µCT scans were obtained prior and at study endpoint 48 h following IT-LPS, to assess emphysema development and muscle mass changes, respectively. Plasma cytokine and GC profiles were determined by ELISA. In vitro, myonuclear accretion and cellular response to plasma and GCs were determined in C2C12 and human primary myotubes. Muscle wasting was exacerbated in LPS-11βHSD1/KO animals compared with WT controls. RT-qPCR and western blot analysis showed elevated catabolic and suppressed anabolic pathways in muscle of LPS-11βHSD1/KO animals relative to WTs. Plasma corticosterone levels were higher in LPS-11βHSD1/KO animals, whereas C2C12 myotubes treated with LPS-11βHSD1/KO plasma or exogenous GCs displayed reduced myonuclear accretion relative to WT counterparts. This study reveals that 11β-HSD1 inhibition aggravates muscle wasting in a model of AE-COPD, suggesting that therapeutic inhibition of 11β-HSD1 may not be appropriate to prevent muscle wasting in this setting.

Item Type:	Journal article
Publication Title:	AJP - Lung Cellular and Molecular Physiology
Creators:	Webster, J.M., Waaijenberg, K., van de Worp, W.R.P.H., Kelders, M.C.J.M., Lambrichts, S., Martin, C., Verhaegen, F., Van der Heyden, B., Smith, C., Lavery, G.G., Schols, A.M.W.J., Hardy, R.S. and Langen, R.C.J.
Publisher:	American Physiological Society
Date:	April 2023
Volume:	324
Number:	4
ISSN:	1040-0605
Identifiers:	Number Type 10.1152/ajplung.00009.2022 DOI 2554731 Other
Rights:	© 2023 The Authors. Licensed under Creative Commons Attribution CC-BY 4.0. Published by the American Physiological Society.
Divisions:	Schools > School of Science and Technology
Record created by:	Melissa Cornwell
Date Added:	13 Jan 2026 14:25
Last Modified:	13 Jan 2026 14:25
URI:	https://irep.ntu.ac.uk/id/eprint/55031

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